Frailty status and its prediction of long-term mortality in patients with Chronic Constipation and Diarrhea

doi:10.21203/rs.3.rs-4813400/v1

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Frailty status and its prediction of long-term mortality in patients with Chronic Constipation and Diarrhea

https://doi.org/10.21203/rs.3.rs-4813400/v1

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Frailty is an emerging health burden but its effect on bowel disorders is unclear. We obtained comprehensive data from the 2009–2010 NHANES and linked mortality data from National Death Index 2019. Frailty was defined by the frailty index composed of routine laboratory data (FI-LAB).Logistic regression was used to explore the association between frailty and bowel disorders. Risk factors for death were identified by Cox proportional hazard regression and used for nomogram formation. The prevalence of frailty was higher in CC (58.3%) and CD (47.7%) than in control (30.6%). CC and CD correlated with increased frailty (ORs 2.6 and 2.2) while frail individuals had higher CD (10.1%, P < 0.001) and CC (11.4%, P < 0.001). CC and CD patients with frailty were older and had higher diabetes, depression, anemia, blood transfusion, and higher mortality (16.5% vs. 2.5%, P = 0.01) than non-frail patients. During a median follow-up of 119 months, frailty was independently associated with a higher risk of all-cause mortality (adjusted HR 21.2). We developed a nomogram: Y = 3.814× frailty index + 0.073 × age, showing an AUC of 0.868/0.816 and high consistencies between the predicted and observed survival probability in the training/validation cohorts.

Health sciences/Gastroenterology

Health sciences/Diseases

frailty

chronic constipation༛chronic diarrhea༛bowel disorders

mortality

Bowel disorders are highly prevalent all around the world, where chronic constipation (CC) and chronic diarrhea (CD) are the two most common types. CC and CD affect approximately 10–15% and 1.5%-17% of the global population, respectively^1–3. A study of 26 countries showed that an increasing number of bowel disorders was associated with lower quality of life, higher presence of anxiety and depression, and huge economic burden ^4,5. Of 36 million weighted visits from the National Ambulatory Care Survey, over 4 million visits for bowel disorders occur annually in the US, accounting for at least $350 million in clinic visit costs alone⁵.

Though bowel disorders are mainly treated in outpatient clinics, their severity and long-term outcomes may be underestimated in the current background of accelerated population aging. For instance, about 40% of CC patients are over 65 years old in the world⁶ while one study focused on elderly community residents aged 65–93 yielded a prevalence of CD as 14.2%⁷. These studies suggest that bowel disorders are more common in the elderly than in the general population. Currently, accumulating evidence supports frailty as a good indicator to evaluate aging and its influence on humans and global health burden^8,9. Frailty is a geriatric state of reduced physiological reserve and increased vulnerability to stressors, which increases the risk of adverse outcomes, including falls, hospitalization, and mortality, due to a disorder of multiple interrelated physiological systems^{9– 11}.

Currently, a major obstacle in frailty study is the lack of globally standardized assessment^11,12. The most widely accepted criteria are based on frailty physical phenotype and frailty index (FI) ^13,15. The Frailty index consists of routine laboratory data (FI-LAB) was established by the Canadian Study of Health and Aging (CSHA) cohort based on 21 laboratory variables in older adults for death risk prediction¹⁶. Several studies have confirmed that FI-LAB is feasible, effective, valid, and better than frailty phenotype based on complex, self-reported data for the prediction of mortality^16–18.

Considering the pathologic status of aging, the effect of frailty on chronic bowel disorders needs further exploration, especially under the condition of many common causative factors and mechanisms shared by these two entities, including poor nutrition and chronicity. To date, there is only one cross-sectional analysis reporting the association between frailty and CC in community-dwelling older people, suggesting that constipation should be considered a crucial geriatric syndrome in clinical practice concerning frail older adults¹². However, there are neither extensive, population-based studies evaluating frailty in CC and CD patients nor its effect on patients’ mortality. We collected data from the National Health and Nutrition Examination Survey (NHANES) which has robust and high-quality data with routine monitoring¹³. In this study, we identified subgroups of CC/CD patients, obtained their related mortality with a long medium follow-up period (9.9 years), and constructed a nomogram for mortality prediction.

Study population

Data were extracted from the 2009–2010 NHANES dataset, which uses a complex, stratified, clustered multi-staged probability sampling design to acquire a nationally representative sample of non-institutionalized U.S. civilians. The NHANES survey program is conducted by the National Center for Health Statistics of the Centers for Disease Control. Participants are selected using a stratified multistage probability design with oversampling of certain ethnic and age groups to allow for sample-weighted inference to the U.S. population. All participants provide written informed consent prior to completing the NHANES, and there are no patient identifiers in the publicly available NHANES database. Participants in the NHANES 2009–2010 database were included in this study if they completed the bowel health questionnaire and were 20 years of age or older.

Bowel Health Questionnaire

This questionnaire was completed using a Computer-Assisted Personal Interview System in a Mobile Examination Center Interview Room. Here we used the Bristol Stool Form Scale. The stool consistency scale has been used in a series of studies^3,14. Participants were shown a card with colored pictures and descriptions of the seven Bristol Stool Form Scale types (BSFS; Type 1-Type 7) and asked to ‘Please look at this card and tell me the number that corresponds with your usual or most common stool type.’ The BSFS is a validated tool that assesses stool consistency on a spectrum of seven types³, chronic constipation was defined as a usual or most common stool type of BSFS Type 1 (separate hard lumps, like nuts) or Type 2 (sausage-like, but lumpy) and chronic diarrhea was defined as a usual or most common stool type of BSFS Type 6 (fluffy pieces with ragged edges, a mushy stool) or Type 7 (watery, no solid pieces). The rest were classified as having normal defecation habits^7,15.

Clinical and laboratory evaluations

This survey included demographic data, socioeconomic information, health-related questionnaires, physical examinations, and laboratory tests. The detailed methods used for clinical and laboratory evaluations were described in NHANES. Briefly, co-variables included in this study included: gender, age, race, education, income, systolic blood pressure, diastolic blood pressure, BMI (body mass index), physical activity, alcohol, frequent milk intake, and highest quartile liquid intake. The Patient Health Questionnaire 9 (PHQ-9) was used to identify individuals with depression ¹⁵. Medical comorbidities were calculated based on responses to the Medical Conditions Questionnaire.

Definition of Frailty

In this study, frailty was defined by FI-LAB. We constructed FI-LAB based on 21 variables including 19 routine blood tests and measured systolic and diastolic blood pressure. Laboratory variables were selected according to previous studies¹⁶ including Alb(g/L), AST(IU/L), calcium (mM), creatinine (µM), folate (nM), folate, RBC (nM), fasting blood glucose (mM), hemoglobin (g/L), MCV (fL), ALP (IU/L), Phosphorus (mM), Potassium (mM), total protein (g/L), Sodium (mM), TSH (µIU/L), Thyroxine (T4; nM), T4 Free (pM), WBC (number/L) and BUN (mg/dl). Each variable was labeled as either 1 or 0, with 1 indicating that the values exceeded the normal range or cut off, and 0 indicating that the values were within the normal range. FI-LAB is defined as the sum of all abnormal variables divided by the sum of all considered variables. For instance, if 3 deficits are found out of 30 reviewed deficits, the FI would be 0.1 (3/30). Theoretically, FI-LAB is a continuous variable between 0 and 1 for each subject, a higher score indicates greater frailty¹⁷. The cutoff point (0.23) was utilized in this study ¹⁶.

All-cause mortality and Training/Validation Cohort categorization

The mortality of participants (≥ 20 years) in the NHANES was followed up using the National Death Index records until December 31, 2019. We calculated the follow-up time (month) from the date of examination at the mobile examination center to the date of death or the end of the follow-up period. The patients were divided into the training and validation cohorts with a ratio of 6:4 using the R function “create Data Partition” to ensure that outcome events were distributed randomly between the two cohorts. The training cohort was used to screen variables and construct the model.The validation cohort was used to validate the results obtained using the training cohort.

Statistical analysis

According to the complex nature of the NHANES database’s survey design, we analyzed the data using appropriate sampling weights to represent a nationally representative population level for the entire US. The means ± standard errors or medium of continuous variables and proportions and 95% Confidential Intervals (CIs) of categorical variables were evaluated among comparison groups. We used Chi-square analysis, unpaired Student's t-test, ANOVA to detect statistically significant differences among various groups. Binary logistic regression was used to explore the association between frailty and CC/CD. Univariate and multivariate Cox regression analyses were performed for all variables, and variables with P < 0.05 in both univariate and multivariate Cox regression were identified as independent risk factors which used for nomogram formation. The discrimination and calibration of the nomogram were evaluated using receiver operating characteristic (ROC) analysis, the area under the time-dependent receiver operating characteristic curve (time-dependent AUC), and calibration plots. The statistical significance was set as two-tailed with p at < 0.05. We used The R statistical software (R Foundation for Statistical Computing, Vienna, Austria, version 4.2.0) and SPSS version 22 (SPSS Inc.) for all statistical analyses and plots.

Baseline characteristics and frailty

Out of 10537 subjects who participated in the 2009–2010 US National Health and Nutrition Examination Survey, a total of 758 subjects completed the Bowel Health Questionnaire and met our eligibility criteria (age ≥ 20), and had all the 21 variables needed to establish FI-LAB (excluding pregnant women, colorectal cancer, inflammatory bowel diseases, and coeliac disease), representing approximately 26,437,274 weighted individuals (Supplementary Fig. 1). Finally, we included 638 people with normal bowel habit, 65 with CD, and 55 with CC (Table 1). In our weighted sample, frailty was significantly more prevalent in CC (58.3% vs. 30.6%, P < 0.001) and CD (47.7% vs. 30.6%, P < 0.001) than in normal individuals. The mean frailty index in individuals with CD (0.23 ± 0.10,p = 0.003) or CC (0.23 ± 0.11, p = 0.009) was significantly higher than in normal individuals (0.19 ± 0.09, Table 1). On the other side, frail individuals were more likely to have CC (10.1% vs. 5.2%, P < 0.001) or CD (11.4% vs. 3.9%, P < 0.001) than non-frail individuals (Supplementary Table 2).

CD patients had higher BMI than normal individuals and CC patients. In addition, CD patients had lower albumin and calcium levels, higher WBC, and depression scores than normal individuals. Patients with CD were more likely to feel worse than normal individuals and need to see mental health professionals. Meanwhile, CC patients had lower uric acid and hemoglobin, higher globulin, and depression scores than normal individuals. Additionally, CC Patients were more likely to have anemia and feel worse than normal individuals. (shown in Table 1 and Supplementary Table 1,2,3).

Frailty investigation in chronic constipation and diarrhea patients

In the chronic constipation group, there were 27 patients with frailty and 28 patients without. CC was correlated with an increased risk of frailty compared with normal individuals(OR: 3.167, P < 0.001). After adjusting for various factors such as age, gender, and chronic diseases, CC was an independent risk factor for frailty (Supplementary Table 7). CC patients with frailty were older, more likely to die, to be female, to have higher BMI, and blood transfusion, and more often to receive health care than non-frail patients. Besides, the sedentary time of CC patients with frailty was longer than those without frailty (Table 2 and Supplementary Table 4).

In the chronic diarrhea group, there were 33 patients with frailty and 32 patients without. CD was correlated with an increased risk of frailty compared with normal individuals(OR:2.071, P < 0.001).

After adjusting for various factors, CC was an independent risk factor for frailty (Supplementary Table 7).CD patients with frailty were older and more likely to be female and married, to have diabetes, arthritis, and heart attack, more likely to see mental professionals, have higher BMI, and depression scores, and have longer sedentary time than those without frailty. In addition, CD patients with frailty had higher mortality, and longer sedentary time than patients without frailty (Table 2 and Supplementary Table 4).

When putting CC and CD together as bowel disorders, there were 60/60 patients with/without frailty. Those patients with frailty were older and more likely to die, to be female, to have diabetes, anemia, and blood transfusion, and also receive health care more frequently than non-frail individuals. Those patients with frailty were also more likely to have depression and see mental health professionals. (Table 2 and Supplementary Table 4). In addition, compared to non-frail individuals, frailty was associated with an increased risk of bowel disorders (for CC, OR 3.167, for CD, OR 2.071). After adjusting for age, gender, and multiple chronic diseases, frailty is an independent risk factor for CC/CD (Supplementary Table 8).

Mortality and nomogram

During a median follow-up of 9.9 years (119 months), the all-cause mortalities of CC, CD, and normal individuals were 9.3%,10.5%, and 8.4%, respectively (Table 1, p = 0.87). Nevertheless, bowel disorders (CC/CD) patients with frailty had considerably greater mortality than non-frail patients (16.5% vs. 2.5%, P = 0.01). However, bowel disorders (CC/CD) per se were not associated with increased all-cause mortality (p = 0.77, Table 3). The cumulative death hazard and survival of the study population based on the frailty index at baseline are presented in Fig. 1.

To increase research credibility and applicability, the participants we included were randomly divided into a training cohort and a validation cohort by a ratio of 6:4. The median follow-up was 119 months in the whole population, in the training and validation cohort. After univariate and multivariate Cox proportional hazard regression analysis, we identified age (HR:1.076, P < 0.001) and frailty index (HR: 45.338, P = 0.008) as independent risk factors for mortality (Table 3 and Supplementary Tables 4,5, 6).

Based on frailty index and age, we developed a nomogram to predict mortality in patients with bowel disorders (CC/CD), Y = 3.814× frailty index + 0.073 × age to predict overall survival (Fig. 2). The AUC of 10-year overall survival was 0.868 (95% CI 0.819–0.917) in the training cohort and 0.816 (95% CI 0.748–0.884) in the validation cohort, indicating the satisfactory discriminative ability of the nomogram (Fig. 3). Furthermore, the calibration curves of the nomogram showed high consistencies between the predicted and observed survival probability in both the training and validation cohorts (Fig. 4).

As far as we know, this is the first study to evaluate the relationship between frailty and bowel disorders (CC/CD) in a nationally representative adult sample in the United States, including 473 non-frail and 285 frail adults, representing approximately 26,437,274 weighted individuals. Frailty was significantly more prevalent in CC and CD than in normal individuals. In addition, we found bowel disorders correlated with an increased risk of frailty compared with normal individuals. Conversely, frail individuals were more prone to have CC/CD than non-frail individuals. Frailty and bowel disorders were independent risk factors for each other.

Furthermore, our study is the first to evaluate the prediction capacity of the frailty index consisting of routine laboratory data (FI-LAB) on mortality in bowel disorder patients. One advantage of our study is that it has a medium follow-up period of nearly ten years (119 months), which may help establish an independent association between frailty and all-cause mortality, for the gradual histologic damage and slow progression of frailty and bowel disorders. Intriguingly, we found that most of the variables constructing FI-LAB do not increase mortality risk, whereas albumin even decreased mortality risk (Supplementary Table 6). However, when combined together as FI-LAB, frailty was independently associated with a higher risk of all-cause mortality (aHR, 21.2). Additionally, bowel disorder patients with frailty had a considerably greater mortality rate than non-frail patients (16.5% vs. 2.5%, P = 0.01). These results reinforced the previously raised theory that FI-LAB reflected the health-related deficits at the general level ^19,20.

After multivariate Cox proportional hazard regression analysis, age and frail index were identified to establish a nomogram to predict mortality. To obtain more reliable results, we randomly divided participants into a training cohort and a validation cohort by a ratio of 6:4 to test the accuracy of the nomogram. The AUC of 10-year overall survival was 0.868 in the training cohort and 0.816 in the validation cohort, indicating the satisfactory discriminative ability of the nomogram. Furthermore, the calibration curves of the nomogram showed high consistencies between the predicted and observed survival probability in both the training and validation cohorts. In summary, the nomogram had considerable discriminative and calibrating abilities. Besides, bowel disorders patients with frailty were older and more likely to have diabetes, anemia, depression, and blood transfusion and more often to receive health care than non-frail individuals. These results underscore the necessity of paying attention to bowel disorders patients with frailty.

Frailty is a huge health, social, and economic burden that has grown over the last decades, but is poorly understood and often under-recognized in gut²¹. At present, the impact of frailty on either intestinal function including immune response, permeability, and absorption, or gut microbiota composition has yet mostly unexplored. Frailty occurs when multiple physiological systems decline due to accumulation of cellular damage, that is, a threshold of the homeostatic reserve is exceeded and repair mechanisms are unable to maintain homeostasis²². The gastrointestinal tract has a crucial role in maintaining the homeostasis of a number of physiological processes, including immunological tolerance to foods, gut microbiota, and digestion and absorption of nutrients. This delicate balance is achieved through the complex interaction between the intestinal epithelial cells and innate and adaptive immunity²³. It has been speculated that the detrimental aging-related alterations may also involve the gastrointestinal tract, leading to the inflammatory response²⁴, an impaired intestinal permeability²⁵ and altered gut microbiota^26,27. These mechanisms may trigger the frailty syndrome; however, whether these alterations are the cause or the consequence is unclear. All of these changes coexist and should be seen as a holistic process that affects each other. Given the significant overlap between bowel disorders and frailty, it is important for clinicians to be cautious about frailty screen when treating bowel disorders patients.

There were several limitations that should be acknowledged. First, although there are many advantages to using an extensive, nationally representative database, there are inherent limitations of cross-sectional nature and risk of recall bias in self-reported data. We obtained long-term follow-up mortality by combining NHANES and National Death Index as compensation methods. Second, this study only reported the most common stool consistency and did not assess stool frequency. However, recent studies have recommended using abnormal stool consistency rather than stool frequency to define diarrhea or constipation, as it correlates best with objective measures of whole-gut transit time^29,30.Lastly, results of this study showed that chronic diarrhea patients had lower albumin levels while chronic constipation patients had lower hemoglobin. These manifestations of chronic depletion suggest the possibility of organic lesions, which usually require colonoscopy to rule out, but unfortunately, this examination was not included in this study.

Despite the limitations mentioned above, this is the first study to use a nationally representative sample of the United States to evaluate the relationship between frailty and bowel disorders (CC + CD) and investigate the mortality in these patients. The nomogram to predict long-term mortality have a unique and practical function. This study may raise the public’s awareness of frailty in bowel disorder patients. Gaining insight into frailty could guide preventive strategies, particularly for potentially modifiable risk factors. For instance, a sedentary lifestyle is recognized as a major contributing factor to frailty onset and progression, while physical exercise is known to preserve or improve frailty³⁴. Our study found that frail bowel disorder patients have longer sedentary time than non-frail patients. Frailty can be improved by a structured multicomponent intervention³⁵, future studies may investigate whether bowel disorders can be improved by interventions targeting frailty. Conversely, as bowel disorders are possible reversible clinical conditions for frailty, frailty might be alleviated by optimal management targeting bowel disorders. While our current study design is insufficient to further delve into these issues, future prospective studies with intervention may provide more evidence on longitudinal cross-talks between bowel disorders and frailty in different care environments.

In this US population-based study, frailty as defined by FI-LAB was common and independently associated with significantly higher mortality in bowel disorders patients. Besides, the presence of frailty was associated with chronic diseases and poor mental health. A prognostic nomogram based on the frailty was developed and validated to evaluate the mortality of bowel disorder patients. Frailty should be considered in the treatment approach, especially in the elderly.

Alb

albumin

ALT

alanine transaminase

ALP

alkaline phosphatase

AUC

time-dependent receiver operating characteristic curve

BMI

body mass index

BSFS

Bristol Stool Form Scale types

BUN

urea nitrogen

confidence interval

CSHA

Canadian Study of Health and Aging

chronic constipation

chronic diarrhea

FBD

functional bowel disorder

functional constipation

frailty index

FI-LAB

frailty index composing of routine laboratory data

GGT

γ-glutamyl transferase

gastrointestinal

hemoglobin

hazard ratio

IBS

irritable bowel syndrome

IBS-C

IBS with predominant constipation

IBS-D

IBS with predominant diarrhea

LDH

lactate dehydrogenase

MCV

mean corpuscular volume

NHANES

National Health and Nutrition Examination Survey

NCHS

National Center for Health Statistics

odds ratio

PHQ-9

Patient Health Questionnaire 9

RBC folate

red blood cell folate

TBIL

total bilirubin

triglycerides

T4 free

thyroxine free

TT4

Total thyroxine

TSH

thyroid stimulating hormone

WBC

white blood cell

Declarations

Ethics approval and consent to participate

Approval of the study from the National Center of Health and Statistics Research ethics review board was waived because the research relied on publicly used, de-identified secondary data.

Consent for publication

This manuscript does not contain any individual person’s data in any form.

Competing interests

All authors have completed the ICMJE uniform disclosure form www.icmje.org/ coi_disclosure.pdf and declared: no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

STROBE Statement

The guidelines of the STROBE Statement have been adopted.

Funding

None.

Author Contribution

J.B and Y.R developed the idea and designed this project. S.Z, and W.Z assisted with data analysis and prepared the manuscript; L.X, W.C, and J.G helped to collect data and revised the manuscript. Y.R and S.Z critically revised the manuscript. J.B supervised the whole process of this project. All authors approved the final version of the manuscript. The corresponding authors attest that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Acknowledgement

We are grateful to the NHANES database for publicly providing research data and for the efforts made by the staff to collect data. We gratefully acknowledge the invaluable contributions and kind cooperation of every author in preparing this manuscript.

Data Availability

All NHANES data generated or analysed during this study are available at https://www.cdc.gov.

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Table 1 Baseline characteristics of participants according to Bowel Health Questionnaire from NHANES. Data are shown as the weighted mean ± standard errors or weighted frequency (95% CIs) as appropriate. *p < 0.05; **p < 0.01; # population estimate

	Normal(n=638) 23,221,020^#	Chronic constipation (n=55) 1,576,044^#	Chronic diarrhea (n=65) 167,621^#	p value
Age(year)	50.0±17.4	45.4±15.3	49.6±17.2	0.162
BMI (kg/m2)	28.9±6.5	28.5±5.2	32.4±7.9	0.003*
Gender(%)				0.080
male	52	34.7	52.7
female	48	65.3	47.3
Race(%)				0.009*
MexicanAmerican	9	24.5	17.1
Other Hispanic	6.1	9.9	6.2
Non-HispanicWhite	69.5	45.3	61.6
Non-Hispanic Black	9.8	15.2	14.2
Other Race	5.6	5.1	0.9
Education level(%)				0.078
less than high school	17.9	25.4	33.1
high school or equivalent	22.5	24.6	16.3
greater than high school	59.6	50	50.6
Martial(%)				0.1429
married	58	42.2	50.5
widowed,divorced,separated	18.4	31.9	19.1
never married	14.6	16.6	13
living with partner	9.1	9.3	17.3
Smoke(%)				0.310
Every day	32	41.7	42.7
Some days	7.5	2.1	14.9
Not at all	60.4	56.2	42.4
Alcohol(bottles)	3.14±3.0	3.14±3.0	3.14±3.0	0.374
Milk(%)				0.878
Never	3.2	5.8	0.8
Less than once a week	12.2	14.2	8.3
Less than once a day	33.1	31.1	47.9
Often once a day or more	50.2	48.9	43
Varied	0.6
Don’t know	0.7	5.8	0.8
Frailty index	0.19±0.09	0.23±0.11	0.23±0.10	<0.001**
Frailty (%)				<0.001**
Yes	30.6	58.3	47.7
No	69.4	41.7	52.3
Depression	2.0(0.0~4.0)	3.0(1.0~8.0)	3.0(0.0~6.0)	0.002*
Death(%)				0.871
No	91.6	90.7	89.5
Yes	8.4	9.3	10.5
General health condition(%)				0.004*
Good or more than good	85.2	72.8	71.2
Fire	12.5	24.8	19.7
Poor	2.3	2.4	9.1
Seen mental health professional (%)				0.012*
Yes	6.3	4	17.2
No	93.7	96	82.8

Table 2 Characteristics of chronic constipation, chronic diarrhea, and bowel disorders patients according to frailty at baseline. Data are shown as the weighted mean ± standard errors or weighted frequency (95% CIs) as appropriate. *p < 0.05; **p < 0.01; # population estimate

	Chronic constipation (n=55/1,576,044^#)			Chronic diarrhea (n=65/ 1,676,210^#)			Bowel disorders (n=120/3,252,254^#)
	Non-frail (n=27)	frailty(n=28)	P value	non-frail (n=33)	frailty(n=32)	P value	Non-frail (n=60)	frailty(n=60)	P value
Population estimate	657,431	918,613		875,875	800,335		1,533,305	1,718,948
Age(year)	38.2 ± 15.7	48.3 ± 15.6	0.024*	43.1 ± 14.1	46.7 ± 15.6	<0.001 **	41.0 ± 15.0	47.6 ± 15.6	0.021 *
BMI(kg/m²)	26.4 ± 4.3	31.0 ± 5.7	0.002*	30.4 ± 5.7	35.1 ± 9.3	0.017*	28.7 ± 5.5	32.9 ± 7.9	0.001 *
Depression	2.0(1.0-7.0)	3.5(1.3-8.0)	0.786	2.0(0-5.5)	4.0(0-8.5)	0.265	2.0(0-5.0)	3.0(0-8.0)	<0.001 **
Vigorous activity(days)	2.8 ± 1.6	1.0 ±0	<0.001 **	2.1 ± 1.3	2.9 ± 1.4	<0.001 **	2.3 ± 1.4	2.7 ± 1.5	<0.001 **
Moderate activity(days)	2.5 ± 1.0	2.99 ± 1.0	<0.001 **	2.7 ± 2.0	3.1 ± 2.1	<0.001 **	2.6± 1.7	3.0 ± 1.6	<0.001 **
sedentary(minutes)	295.6 ± 202.5	341.8 ± 149.4	<0.001 **	365.1 ± 192.2	406.4± 210.6	<0.001 **	335.3 ± 199.7	371.8 ± 183.4	<0.001 **
Gender(%)			0.001 **			0.027 *			<0.001 **
male	63.9	13.8		65.8	38.5		65	25.3
female	36.1	86.2		34.2	61.5		35	74.7
Race(%)			0.0544			0.814			0.243
Mexican American	36.2	16.1		15.6	18.8		24.5	17.3
Other Hispanic	10.3	9.5		5.9	6.6		7.8	8.1
NonHispanic White	26.3	59		66.4	56.4		49.2	57.8
Non-Hispanic Black	14.9	15.4		10.4	18.3		12.3	16.8
Other Race	12.2			1.6			6.2
Education (%)			0.060			0.511			0.284
less than high school	25.1	25.6		26.9	39.7		26.2	32.2
high school /equivalent	40	13.6		16.3	16.4		26.5	14.9
greater than high school	34.9	60.9		56.8	43.8		47.4	52.9
Marital			0.372			0.035 *			0.054
married	34.2	47.9		39.6	62.4		37.3	54.7
Widowed/divorced/separated	29.9	33.3		28.9	8.4		29.4	21.7
never married	26.8	9.3		19.4	6.1		22.6	7.8
living with partner	9	9.5		12	23.2		10.8	15.9
Smoke(%)			0.438			0.306			0.212
Every day	55.5	26.8		56.4	34.7		56	32.4
Some days	44.5	4.3		17.5	13.3		10.2	10.8
Not at all		68.9		26.1	52		33.8	56.8
Death(%)			<0.001 **			<0.001 **			<0.001 **
no	96.3	86.6		98.4	79.8		97.5	83.5
yes	3.7	13.4		1.6	20.2		2.5	16.5

Table 3 Survey-weight adjusted univariable and multivariable Cox proportional analysis for mortality in bowel disorders patients.

Univariate Cox regression						Multivariate Cox regression
Variables	B	HR	95.0% CI HR		P value	B	HR	95.0% CI HR		P value
Gender	-0.652	0.521	0.165	1.642	0.266
AGE	0.087	1.091	1.066	1.117	<0.001 **	0.071	1.076	1.045	1.108	<0.001 **
Race					0.738
Mexican American	-12.846	0	0	.	0.983
Other Hispanic	0.643	1.902	0.455	7.963	0.379
Non-Hispanic White	1.076	2.933	0.656	13.109	0.159
Non-Hispanic Black	-12.846	0	0	.	0.994
Education					0.843
education(1)	-0.432	0.649	0.131	3.218	0.597
education(2)	-0.262	0.77	0.217	2.728	0.685
Frailty index	7.603	2003.909	184.828	21726.407	0.003*	3.814	45.388	2.733	752.202	0.008*
Alcohol	-0.386	0.68	0.348	1.328	0.258
Asthma	0.774	2.169	0.225	20.867	0.503
Anemia	-0.02	0.98	0.126	7.591	0.984
Blood transfusion	-0.552	0.576	0.126	2.63	0.477
Arthritis	-1.082	0.339	0.109	1.052	0.061
Gout	-1.505	0.222	0.029	1.723	0.150
Heart failure					<0.001 **					0.170
yes	0.245	1.278	0.165	9.902	0.815	0.363	1.437	0.097	21.279	0.792
no	-2.006	0.135	0.019	0.97	0.047	-0.751	0.472	0.03	7.308	0.591
Heart attack	-1.184	0.306	0.039	2.372	0.257
Stroke	-3.013	0.049	0	26677638928	0.827
Coronary heart disease					0.004*					0.661
yes	-1.371	0.254	0.053	1.225	0.088	-0.882	0.414	0.049	3.498	0.418
no	-2.561	0.077	0.019	0.316	0	-0.945	0.389	0.05	2.999	0.365
bowel disorders	-0.171	0.843	0.267	2.655	0.770

No competing interests reported.

supplementarytable1.docx
Table S1 Baseline characteristics of participants according to Bowel Health Questionnaire from NHANES.
supplementarytable2.docx
Table S2 Baseline characteristics of participants according to frailty status.
supplementarytable3.docx
Table S3 Laboratory indexes of participants according to Bowel Health Questionnaire from NHANES.
suplementarytable4.docx
Table S4 Characteristics of chronic constipation, chronic diarrhea, and bowel disorders patients according to frailty at baseline.
supplementarytable5.docx
Table S5 Univariable Cox proportional analysis for mortality in bowel disorders patients.
supplementarytable6.docx
Table S6 Univariable Cox proportional analysis （Laboratory indexes）for mortality in bowel disorders patients.
supplementarytable7.docx
Table S7 Univariate and multivariate Binary logistic regression for frailty.
supplementarytable8.docx
Table S8 Univariate and multivariate Binary logistic regression for bowel disorders.
supplementaryfigure1.png
Figure S1 Flow chart for inclusion of the subjects.

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Frailty status and its prediction of long-term mortality in patients with Chronic Constipation and Diarrhea

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Abstract

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Introduction

Methods

Study population

Bowel Health Questionnaire

Clinical and laboratory evaluations

Definition of Frailty

All-cause mortality and Training/Validation Cohort categorization

Statistical analysis

Results

Baseline characteristics and frailty

Frailty investigation in chronic constipation and diarrhea patients

Mortality and nomogram

Discussion

Conclusion

Abbreviations

Declarations

Declarations

Competing interests

STROBE Statement

Funding

Author Contribution

Acknowledgement

Data Availability

References

Tables

Additional Declarations

Supplementary Files

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